Bionic heart tissue: U-Michigan part of $20M center Scar tissue left over from heart attacks creates dead zones that don’t beat. Bioengineered patches could fix that.

The University of Michigan is partnering on an ambitious $20 million project to grow new heart tissue for cardiac patients. The new research center has been awarded to Boston University (BU), with strong partnership from U-M and Florida International University (FIU).

“A heart attack creates scar tissue, and the heart never returns to full function. But for every person, we could create a living patch that a surgeon could stitch in,” said Stephen Forrest, who leads the nanotechnology aspect of the project and is U-M’s Peter A. Franken Distinguished University Professor of Engineering. “It’s very audacious.”

The project is a National Science Foundation Engineering Research Center. These 5-year grants are typically renewed for another 5 years, so the researchers are looking at a 10-year timeline to go from the current state of tissue engineering to working, implantable heart tissue.

A heart attack creates scar tissue, but we could create a living patch that a surgeon could stitch in.Steve Forrest

“Heart disease is one of the biggest problems we face,” said David Bishop, director of the new center and a BU professor of electrical and computer engineering and physics. “This grant gives us the opportunity to define a societal problem, and then create the industry to solve it.”

The living patches the researchers are developing would consist of heart muscle cells, blood vessels to carry nutrients in and waste out, and optical circuitry to make the heart muscle cells beat in synchrony. Already, researchers in the lab have been developing ways to structure cells in scaffolds that mimic particular organs and grow blood vessels into artificial tissues. But typically, working implants have been static, biodegradable materials such as artificial windpipes that the body gradually replaces with tissue. Working tissue, like heart muscle, would need to be responsive as soon as it was implanted.

Engineering Research Center grants are extremely competitive, with only four of more than 200 applicants receiving an award in 2017. These centers are designed to work directly with industry to translate breakthroughs along the way out of the lab and into healthcare. Just producing a more true-to-life “heart on a chip” could aid the pharmaceutical industry in developing better treatments for problems such as arrhythmia.

Ramcharan and her colleagues in Lahann’s lab will help design and produce a polymer-protein construct that mimics the 3D matrix connecting the cells in human heart muscle. Heart muscle cells moving into this environment will then be able to link up into a single tissue. Photo: Joseph Xu, Michigan Engineering Communications & Marketing.

In order to produce the heart tissue, the team intends to start with an artificial scaffold that mimics the 3D structure of heart tissue. Joerg Lahann, a U-M professor of chemical engineering, will work with the team building the flexible polymer scaffold, as well as on the attachment and monitoring of cells within that framework.

“Michigan is pleased to lend expertise to the development of implantable heart tissue, which could improve and extend so many lives,” said Alec D. Gallimore, the Robert J. Vlasic Dean of Engineering. “Our faculty members are leaders in nanotechnology and in developing materials that support and interact with living cells and tissues, two areas that are critical to the project’s success.”

The 3D scaffold will initially be peppered with nanometer-sized gold patches that act as attachment points for protein fragments, called peptides, which will then serve as anchors for the cells. They will be printed onto the gold patches using a technique developed by Forrest and Max Shtein, a U-M associate professor of materials science and engineering. This method, called organic vapor jet printing, was initially invented for mass-producing electronic devices.

“The adaptation of this technology to biological systems represents a radically new step,” said Forrest. U-M will receive $2.8 million for these contributions.

Christopher Chen, the center’s director of cellular engineering and a BU professor of biomedical engineering, will lead the effort to grow heart muscle cells on the scaffold and infuse the tissue with blood vessels. Meanwhile, Alice White, director of nanomechanics and chair of the BU mechanical engineering department will work closely with Arvind Agarwal, an FIU professor of mechanical and materials engineering, to produce an artificial nervous system that uses light to synchronize the heartbeat in the tissue.

Stacy Ramcharan, a doctoral student in chemical engineering, uses a computerized system to layer polymer fibers, forming a scaffold for growing cells into artificial tissues. Photo: Joseph Xu, Michigan Engineering Communications & Marketing.

“It’s humbling to have the opportunity to work on something that could really be a game changer,” says Bishop. “If we succeed, we’ll save a lot of lives and add meaningful years for many people.”

In addition to the technical thrusts led by Forrest, Chen and White, Thomas Bifano, a professor of mechanical engineering and director of BU’s Photonics Center, will direct imaging.

Along with the core partners, Harvard Medical School, Columbia University, the Wyss Institute at Harvard, Argonne National Laboratory, the École Polytechnique Fédérale de Lausanne in Switzerland, and the Centro Atómico in Argentina will offer expertise in bioengineering, nanotechnology, and other areas.

Forrest is also the Paul G. Goebel Professor of Engineering, and a professor of electrical engineering and computer science, material science and engineering, and physics. Lahann is also a professor of material science and engineering, biomedical engineering, and macromolecular science and engineering. Shtein is also an associate professor of chemical engineering, macromolecular science and engineering, and art and design. Gallimore is also the Richard F. and Eleanor A. Towner Professor, an Arthur F. Thurnau Professor, and a professor of aerospace engineering.

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‘Sister cell’ profiling aims to shut down cancer metastasis Michigan engineers release individual cells from a specially-designed chip using laser pulses.

In work that could improve understanding of how cancer spreads, a team of engineers and medical researchers at the University of Michigan developed a new kind of microfluidic chip that can capture rare, aggressive cancer cells, grow them on the chip and release single cells on demand.

For the first time, they can easily compare two different “sister” cells – born of the same original cancer cell – to explore how different genes are activated and deactivated as cancer cells divide and spread. Studies with the new chip could also reveal why some cancer cells are resistant to drugs.

Scientist at work in a dark lab

IMAGE:  Yu-Chih Chen views the chip through a microscope. Photo: Evan Dougherty, Michigan Engineering

The ultimate goal of the project – led by Euisik Yoon, a professor of electrical engineering and computer science and corresponding author on the paper in ACS Nano – is to find out what drives the “self-renewal” processes that enable these aggressive cancer cells to behave like stem cells. These cells are known as cancer stem cells – they are capable of dividing and turning into different kinds of cancer cells, with different genes turned on or off. Cancer researchers believe that if the stem-like properties can be switched off, the cancer will not be able to grow and spread.

“When a tumor forms, some cancer stem cells maintain stemness, while others are differentiated. By understanding this, we will know more about tumor formation and discover ways to inhibit it,” said Yu-Chih Chen, a research scientist in electrical engineering and computer science and co-first-author on the paper.

The base of the new chip is composed of carbon nanotubes covered in a plastic coating. When a cancer cell settles on the chip, it sticks itself to that coating. To release the cell, the researchers shone extremely short pulses of laser light near it. The light is readily absorbed by the carbon nanotubes, flash-heating them, while the plastic insulates the cell.

The heat causes trapped air between the nanotubes and plastic to expand, blowing a bubble under the cell. When the bubble bursts through the plastic, the cell detaches. Then, the cell can be flushed out of the chip and captured for genetic profiling.

Gif showing lasers releasing the cell

IMAGE:  The laser creates a bubble under the cell that bursts out and releases the cell so that it can flow out of the chip. Yu-Chih Chen, Yoon Lab, University of Michigan.

Most existing methods for freeing individual captured cancer cells are either damaging to the cells or else cannot get them out of the chip reliably. The laser was precise enough that it could detach one side of a cell, leaving the other side anchored.

And the bubble detachment process was so gentle that even surface proteins on the cell membrane were unscathed. The surface proteins are an important nondestructive avenue for identifying cancer stem cells.

To begin exploring the differences in gene expression between sister cells, the team first looked at a gene called Notch, which is associated with both normal and cancerous stem cells. If Notch was expressed in the daughter cells, it was a rough indication that the division was self-renewing. A Notch-positive cell could go on to produce two cells expressing the same gene, one Notch-positive and one Notch-negative, or two Notch-negative cells.

Their analyses demonstrated that Notch does not serve as a sole indicator for a cancer cell’s stem-like properties. Other genes associated with stem cells could be switched on or switched off in daughter cells with either Notch expression.

Some cells are very resistant; some are easily killedEuisik Yoon, EECS

The task ahead of cancer researchers, with the help of the new chip, is to identify which of these genes are critical to a cancer stem cell’s self-renewing capabilities. If these can be shut down, forcing all cancer stem cells to produce only non-stem cells when they divide, it may be possible to subvert a tumor’s ability to grow and spread.

“If we identify some key genes, or a potential drug target, then pharmaceutical researchers can develop a compound to hit this drug target,” said Chen.

Drug testing inspired Yoon to develop this chip. On earlier chips, some cancer survived treatments, and he wanted to understand these cells better.

“Some cells are very resistant; some are easily killed,” said Yoon. “We wanted to take individual cells out after drug screening and look at their genetic profiles to see if we can see what makes cancer cells stem-like.”

Future experiments could lead to what some cancer researchers call “functional cures,” similar to the management of HIV. The cancer doesn’t necessarily have to be eradicated. Stopping the cancer from spreading may be enough to enable a cancer patient to live a healthy life.

This work is reported in a paper titled “Selective photo-mechanical detachment and retrieval of divided sister cells from enclosed microfluidics for downstream analyses”, appearing today in ACS Nano.

The study was funded in part by the Department of Defense and the National Institutes of Health.

Euisik Yoon is also a professor of biomedical engineering.

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